Water-soluble composition containing coenzyme q10

ABSTRACT

A water-soluble composition comprising (A) coenzyme Q 10  of 5-40% by weight, (B) monoester of polyglycerol with average polymerization degree of 10 and fatty acid with 18 carbon atoms of 5-30% by weight, (C) mono-, di-, tri- or penta-ester of polyglycerol with average polymerization degree of 3-6 and fatty acid with 18 carbon atoms of 1-18% by weight, and (D) water, wherein its average particle diameter is 110 nm or smaller. It is superior in acid resistance, salt-resistance and heat resistance, and further enables to maintain the good water-soluble state being blended to medicines, foods and beverages, cosmetics, feeds, additives usually employed therein.

TECHNICAL FIELD

The present invention relates to a water-soluble composition containingcoenzyme Q₁₀. The invention further relates to a process for producingthe water-soluble composition, medicines, foods and beverages, cosmeticsand feeds containing the water-soluble composition. Specifically, theinvention relates to water-soluble composition capable of containingcoenzyme Q₁₀ with high concentration, superior in storage stability suchthat coenzyme Q₁₀ will not precipitate, deposit or float during a longterm preservation, and also superior in absorbency such that it givesabsorbency even under fasting. Furthermore, the invention relates tomedicines, foods and beverages, cosmetics and feeds comprisingcomposition containing coenzyme Q₁₀ superior in heat resistance, acidresistance and salt-resistance that are required for the application.

BACKGROUND ART

Coenzyme Q₁₀ corresponds to ubiquinones (formula: C₅₉H₉₀O₄; molecularweight: 863.4) that is2,3-dimethoxy-5-methyl-6-polyprenyl-1,4-benzoquinone with a side-chaincomprising 10 isoprene units, and existing in higher animal. It is onekind of coenzyme Q known as ubidecarenone or coenzyme Q₁₀. The physicalproperty of coenzyme Q₁₀ is known as orange crystal, which is afat-soluble substance having melting point at about 49° C. Coenzyme Q₁₀is known as not only a coenzyme having biological activity but also avitamin-like active substance having function of improving oxygenutilization efficiency. Coenzyme Q₁₀ is considered to be essential inproduction of adenosine triphosphate in mitochondria, and it is reportedto be effective for the treatment of cardiac disease, hypertension,rheumatic valve affection or inflammation of alveolar each by improvingits immune function. It is also employed for the treatment of congestiveheart failure or cerebrovascular disorder, for prevention of adverseeffects of anticancer agents (prevention of cardiopathy by adriamycin),for fatigue reactivation, for energy activation, and for antioxidationof in vivo active oxygen. Its validity to prevent from aging employed asskin external preparation is expected, too. Thus, coenzyme Q₁₀ has highbioactivity and it is believed as highly safe substance existing invivo.

In late years, various kinds of technology are disclosed regardingcoenzyme Q₁₀ under such situations.

For example, JP-A-60-199814 discloses a fatty emulsion obtained byprocessing nonionic surfactant such as polyethylene glycol, hardenedcastor oil polyoxyethylene-(20)-ether and so on with Manton Gaulin typehigh pressure homogenizer (500 to 550 kg/cm²).

JP-A-63-150221 discloses an emulsified composition for pharmaceuticalmedicines with excellent absorbency obtained by employing ubiquinone ascrystalline agent, dissolving it into adipic acid or an oil such assoybean oil and so on in supersaturated condition, preparing O/W typemicroemulsion with the use of surfactant such as polyoxyalkylene base,polyglycerol fatty acid ester, Tween base or so, and by adding anotherO/W type microemulsion.

EP-494651B1 and U.S. Pat. No. 5,298,246 disclose a composition withimproved absorbency prepared by dissolving ubiquinone into oil,emulsifying with the use of a fat globule membrane in mammals milk, andby fractionating particles of specified particle diameter (1-5 μm).

JP-A-2000-212066 discloses aqueous emulsion containing fat-solublesubstance prepared by combining ubiquinone as lipid-soluble substance,polyglycerol fatty acid ester as emulsifier and glycerol-phosphoriclipid, further adding polyalcohol and water, and then stirring, followedby homogenization processes with high pressure of 500-2000 kg/cm².

Coenzyme Q₁₀ fat emulsion described in JP-A-60-199814 has problems thatits particle size is large and that it is inferior in transparency.

The composition disclosed in EP-494651B1 and U.S. Pat. No. 5,298,246wherein coenzyme Q₁₀ is necessarily dissolved in oil has problems thatits particle diameter is large and that it is inferior in transparency.Besides, there is problem that it is inferior in heat resistance, acidresistance and salt-resistance each needed for manufacturing foods andbeverages.

JP-A-63-150221 further teaches cosmetic liquid that is superior instorage stability under low temperature, however in this technology,transparency becomes poor and precipitation occurs along with decreaseof the liquid temperature, and there is problem that it is inferior inheat resistance, acid resistance and salt-resistance each needed formanufacturing foods and beverages.

JP-A-2000-212066 also teaches oil-in-water type microemulsion applicableto various kinds of oily substances. However, this technology hasproblems of being inferior in acid resistance, salt-resistance and heatresistance under various conditions.

JP-A-9-168369 discloses a solubilized oil and fat composition containingpolyglycerol fatty-acid ester, water and food additives. However, thecomposition has problems of being inferior in transparency andstability.

A water-soluble composition containing coenzyme Q₁₀ is expected tosatisfy the following requirements:

(1) small particle sizes, and superior in transparency;

(2) high concentration of coenzyme Q₁₀ without needing oil componentsfor dissolving or dispersing;

(3) superior in a feeling of delicious dining and taste;

(4) without needing special conditions or complicated processes inmanufacturing; and

(5) superior acid-proof heat resistance and salt-tolerant heatresistance which are necessary for addition into various food.

However, formulation of coenzyme Q₁₀ by emulsification is generallyaccompanied by difficulty because coenzyme Q₁₀ is insoluble in water,instable against light, heat or alkali, and high crystallinity. Further,even once after preparing emulsion, the problem that separation,deposition, precipitation or floating will occurs by there-crystallization of coenzyme Q₁₀. Although the concentration ofcoenzyme Q₁₀ in water-soluble compositon is needed to increase to getsufficient effect of coenzyme Q₁₀, it is difficult to aqueouslysolubilize because of its dissolution retardency and high crystallinity.

Moreover, a solubilized solution without requiring an ordinary oilycomponent in an occasion of adding coenzyme Q₁₀ in foods and beverages,cosmetics or so; superior in transparency, acid resistance,salt-resistance and heat resistance that are altogether necessary whenblending with the foods and beverages, cosmetics or so; excellent inemulsion stability and storage stability; further capable of containingcoenzyme Q₁₀ with high concentration was eagerly demanded. Stillfurther, improving absorbency of coenzyme Q₁₀ was also demanded becausethe in vivo absorbency was poor.

Accordingly, the present invention has an object of overcoming the aboveproblems and providing a water-soluble composition containing coenzymeQ₁₀ and a process for producing thereof without employing solvent suchas oils, superior in storage stability such that coenzyme Q₁₀ will notprecipitate, deposit or float during a long term preservation, alsosuperior in texture, taste, acid resistance, salt-resistance, heatresistance in an occasion of addition into medicines, foods andbeverages, cosmetics and feeds; and further improving bioabsorbencyconspicuously. Another object of the invention is to provide medicines,foods and beverages, cosmetics and feeds together with theiradministration superior in transparency even after blending thecomposition into them without deposition, precipitation, or floating ofcoenzyme Q₁₀.

DISCLOSURE OF THE INVENTION

As the result of intensive researches and studies to achieve the aboveobject by the present inventors, it was found that forming oil-in-watertype emulsion with the use of two kinds of specific surfactant will keepexcellent solubilized states of coenzyme Q₁₀ in high concentration andwill improve bioabsorbency, resulting in completion of the invention.

Namely, the invention provides the following [1] to [8]:

[1] A water-soluble composition comprising (A) coenzyme Q₁₀ of 5-40% byweight, (B) monoester of polyglycerol with average polymerization degreeof 10 and fatty acid with 18 carbon atoms of 5-30% by weight, (C) mono-,di-, tri- or penta-ester of polyglycerol with average polymerizationdegree of 3-6 and fatty acid with 18 carbon atoms of 1-18% by weight,and (D) water, where its averaged particle diameter is 110 nm orsmaller;

[2] The water-soluble composition of item [1], wherein the fatty acidcomposing component (B) is stearic acid, oleic acid or linoleic acid,and wherein the fatty acid composing component (C) is stearic acid,oleic acid or linoleic acid;

[3] The water-soluble composition of item [1] or [2], further comprising(E) solubilizer of 10-80% by weight.

[4] The water-soluble composition of item [3], wherein the solubilizeris gums, saccharides or polyhydric alcohol;

[5] The water-soluble composition of item [1], wherein a weight ratio of[(A)]/[(B)+(C)] is within the range of 1/(5-0.7) and wherein a weightratio of [(B)]/[(C)] is within the range of 1/(0.2-1);

[6] A process for producing the water-soluble composition according toitem [1] which comprises the steps of:

(I) heating and dissolving components (B), (C), (D) and optionally thecomponent (E);

(II) adding component (A) and mixing; and at least one selected from

(III) homogenizing the resultant mixture with a shear force of 750m/minute or greater as a peripheral-speed of an agitation blade using ahomo-mixer; or

(IV) homogenizing the resultant mixture under a homogenizing pressure of98 MPa (1,000 kg/cm²) or greater using a homogenizer.

[7] The process of item [6], wherein the step (III) or (IV) is repeated,or wherein the steps (III) and (IV) are successively carried out.

[8] Medicines, foods and beverages, cosmetics and feeds containing thewater-soluble composition of item [1].

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which illustrating the absorbency of coenzyme Q₁₀ infasting intake.

FIG. 2 is a graph which illustrating the absorbency of coenzyme Q₁₀ inafter-meal intake.

THE PREFERRED EMBODIMENT TO CARRY OUT THE INVENTION

The present invention relates to a water-soluble composition whichcomprises (A) coenzyme Q₁₀ of 5-40% by weight, (B) monoester ofpolyglycerol with average polymerization degree of 10 and fatty acidwith 18 carbon atoms of 5-30% by weight, (C) mono-, di-, tri- orpenta-ester of polyglycerol with average polymerization degree of 3-6and fatty acid with 18 carbon atoms of 1-18% by weight, (D) water, andoptionally (E) solubilizer of 10-80% by weight, wherein averagedparticle diameter is 110 nm or smaller, preferably 80 nm or smaller, andmore preferably 60 nm or smaller.

Component (A)

Coenzyme Q₁₀ as the component (A) is described as ubiquinone 10,ubidecarenone or coenzyme UQ₁₀ in Japanese pharmacopoeia. Coenzyme Q₁₀employed in the present invention may be extracted from the heart ofanimals such as cattle or so, and it may be prepared through a syntheticmethod or a fermentation method. Specific examples of the commerciallyavailable coenzyme Q₁₀ include food material coenzyme Q₁₀ (Nissin PharmaInc.), Kaneka coenzyme Q₁₀ (Kaneka Corporation), CoEnzyme Q₁₀ (AsahiKasei Corporation), etc. Although a purity of coenzyme Q₁₀ is notparticularly specified depending on the application, impurity and itscontents, or quality of the products must be sufficiently under controldepending on the utilization because the water-soluble composition ofthe present invention is applied to medicines, beverages and foodsincluding various supplements or so, and cosmetics.

An amount of coenzyme Q₁₀ in the composition is within the range of5-40% by weight, preferably 7-30% by weight, and more preferably 9-25%by weight.

When the amount of coenzyme Q₁₀ is smaller than 5% by weight, it is notfavorable because the quantity of the water-soluble composition willincrease in order that the aimed effect is achieved. When the content ofcoenzyme Q₁₀ exceeds 40% by weight, it is also unfavorable becausemaintaining solubilized states of coenzyme Q₁₀ in the composition willbecome difficult.

Component (B)

An amount of component (B), i.e., monoester of polyglycerol with averagepolymerization degree of 10 and fatty acid with 18 carbon atoms iswithin the range of 5-30% by weight. Preferably the amount may be withinthe range of 5-25% by weight, more preferably within the range of 7-20%by weight from the viewpoint of emulsion stability or flavor.

The fatty acid composing component (B) is not particularly limited asfar as the fatty acid has 18 carbon atoms, preferably stearic acid,oleic acid, linoleic acid or so may be employed.

Accordingly, decaglycerinmonostearate, decaglycerimonooleate,decaglycerinmonolinoleate or so is preferable as the monoester ofcomponent (B), but not limited thereto. Further, any mixture of theabove monoesters may be employable.

Such a monoester of polyglycerol and C18 fatty acid is commerciallyavailable, and the examples include Sunsoft Q-18S, Sunsoft Q-17S (TaiyoKagaku Co., Ltd.), Poem J-0381 (Riken Vitamin Co., Ltd.), SY-GlysterMO-750, FRL-1 (Sakamoto Yakuhin Kogyo Co., Ltd.), O-15 D(Mitsubishi-Kagaku Foods Cooperation).

The purity of the monoester is not particularly limited, and it mayinclude a certain amount of di-ester and tri-ester besides polyglycerolfatty acid monoester with average polymerization degree of 10considering the production thereof.

Component (C)

An amount of component (C), i.e., polyglycerol with averagepolymerization degree of 3-6 and mono-, di-, tri- or penta-ester with 18carbon atoms is within the range of 1-18% by weight, preferably 2-18% byweight, more preferably 3-9% by weight from the viewpoint of emulsionstability or flavor.

The fatty acid composing component (C) is not particularly limited asfar as the fatty acid has 18 carbon atoms, preferably stearic acid,oleic acid, linoleic acid or so may be employed.

Examples of polyglycerol ester with average polymerization degree of 3-6include mono-, di-, tri- and penta-ester of C18 fatty acid andtriglycerin, tetraglycerin, pentaglycerin, or hexaglycerin. Particularlypreferable example is pentaglycerin monoester.

The glycerin part is polyglycerol with average polymerization degree of3-6, and a mixture thereof is also employable.

Examples of mono-, di-, tri- or penta-ester of polyglycerol and fattyacid composing component (C) include mono-, di-, tri- or penta-stearateof tri-, tetra-, penta- or hexa-glycerin; mono-, di-, tri- orpenta-oleate of tri-, tetra-, penta- or hexa-glycerin; mono-, di-, tri-or penta-linoleate of tri-, tetra-, penta- or hexa-glycerin; and thesemixture may be also employable.

Such esters of polyglycerol and C18 fatty acid are commerciallyavailable, and the examples include SY-Glysters MS-310, TS-310, MO-310,PO-310, MS-500, PS-500, MO-500 and PO-500 (Sakamoto Yakuhin Kogyo Co.,Ltd.), Sunsofts Q-18F, Q-17F, A-181C, A-171 C, A181E, A171E, A-183E andA-173E (Taiyo Kagaku Co., Ltd.) and Poem J-4581 (Riken Vitamin Co.,Ltd.), etc.

The purity of the polyglycerol fatty acid ester is not particularlylimited, and it may include two or more ester considering the productionthereof.

Further, the surfactants such as components (B) and (C) are notnecessarily required as highly purified by distillation, but may be areaction mixture.

In the water-soluble composition of the present invention, it ispreferable that a mixing ratio of/(weight ratio) is 1/(5-0.7), and thata mixing ratio of (weight ratio) is 1/(0.2-1) in order to prepare astable water-soluble composition.

Component (D)

The component (D), i.e. water, is not particularly limited as far aswater is capable of blending to medicines, foods and beverages,cosmetics or feeds; and examples include ion-exchange water, purifiedwater such as distilled water or so, tap water, natural water, alkaliion water. Further, water used therein may contain food additives.Examples of the additives include vitamins, surfactants, stabilizers,seasonings, acids and salts.

Component (E)

Examples of the solubilizer as component (E) include gums, glycitol,saccharides and so on having function of stabilizing solubilized stateof coenzyme Q₁₀. Specific examples include gums such as gum arabic,xanthan gum, tragacanth gum, guar gum, gellan gum, locustbean gum;polyalcohol such as ethylene glycol, propylene glycol, glycerin,erythritol and so on; monosaccharide and disaccharide such as multitol,restored starch syrup, Lactitol, Palatinit, sorbitol, mannitol,glucose-fructose liquid sugar and milk sugar; and polysaccharides suchas dextrin. These solubilizers may be used alone or in combination oftwo or more kinds thereof. Preferably the solubilizer are reducingsaccharides such as glucose-fructose liquid sugar due to sweetness, andgums such as arabia gum due to flavor.

A blending amount of the solubilizer is within the range of 10-80% byweight, preferably 10-70% by weight, and more preferably 15-60% byweight. When the amount of the solubilizer exceeds 80% by weight, theblending content of coenzyme Q₁₀ or the surfactants decreases resultingin undesirable difficulty of providing the effect of coenzyme Q₁₀ andpreparing stable water-soluble composition.

In the invention, one or more other surfactant may be used incombination as far as it does not obstruct the effect of the invention,in addition to (B) polyglycerol fatty acid monoester and (C)polyglycerol fatty acid mono-, di-, tri- or penta-ester. Examples of thesurfactants include polyglycerol fatty acid ester other than components(B) and (C), organic acid monoglyceride, glycerin fatty acid ester,sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylenesorbitan fatty acid ester (polysorbate), propylene glycol fatty acidester, lecithin, enzymatic hydrolysis lecithin, saponin, sterol, cholicacid, deoxycholic acid, yucca extract, cationic surfactant, anionicsurfactant, ampholytic surfactant, nonionic surfactants other than theabove.

A process for producing the water-soluble composition of the presentinvention will be explained below.

The invention relates to a process for producing the water-solublecomposition which comprises the following steps of (I), (II), (III)and/or (IV).

Step (I):

Weighing defined amounts of the components (B), (C), (D) and optionallycomponent (E) respectively, heating and dissolving. For example, it ispreferable to heat and dissolve with agitating using three-one-motor orso in a water bath at 60-80° C.

Step (II):

Adding component (A), i.e., coenzyme Q₁₀, and mixing.

Step (III):

Homogenizing with the shear force of at least 750 m/minute expressed asa peripheral-speed of an agitation blade using a homo-mixer.

Step (IV):

Homogenizing and under a pressure of at least 98 MPa (1,000 kg/cm²)using homogeneizer.

By the above steps, the average particle diameter of coenzyme Q₁₀ whichis oil-in-water type emulsion in the composition of the invention become110 nm or smaller, preferably 80 nm or smaller, and more preferably 60nm or smaller.

When the average particle diameter exceeds 110 nm, storage stability ofthe composition, the bioabsorbency and transparency are not sufficient,and the effect of the invention may be not achieved.

Moreover, the average particle diameter is desirably 60 nm or smaller inorder to improve the bioabsorbency of coenzyme Q₁₀.

Examples of the homo-mixer used in the homogenization treatment of thestep (III) include T.K. HOMO MIXER (TOKUSHU KIKA KOGYO Co., Ltd.), ClearMIX (M Technique Co., Ltd.). Applying high shear force agitating withthe agitating blade at a peripheral-speed of 750 m/minute or greater,preferably 1000 m/minute or greater, and more preferably 1500 m/minuteor greater represents the homogenization method.

Examples of the high pressure homogenizer used for the homogenization ofthe step (IV) include Microfluidizer (MIZUHO Industrial Co., Ltd.),Ultimaizer (Sugino Machine Limited), etc. The high shear force of 98 MPa(1,000 kg/cm²) or greater, preferably 150 MPa (1531 kg/cm²) or greater,more preferably 200 MPa (2039 kg/cm²) or greater is employed for thehomogenization in the step (IV).

Repeating the homogenization of the step (III) or (IV) alone orperforming the steps (III) and (IV) successively enables to provide ahomogeneous liquid water-soluble composition containing coenzyme Q₁₀.This homogenization procedure preferably conduct twice or more in orderto provide a more fine and stable water-soluble composition of coenzymeQ₁₀.

Further, various homogenizers such as Nanomizer, ultrasonic emulsifierand various homo-mixers such as AGI HOMO MIXER, Ultra Mixer or so arealso employable for the homogenization.

The process for producing the water-soluble composition of theinvention, may comprise a natural emulsification method, phase inversionemulsification method, liquid crystal emulsification method, gelemulsification method, D phase emulsification method or PITemulsification method may be applicable. Moreover, the process of theinvention may conduct these methods in combination with mechanicalemulsification method such as the foregoing homogenization, etc.

Optionally, oil, lipid, and other oily components that are employablefor foods may be blended because coenzyme Q₁₀ is an oily component.Examples of the oil employable for foods, include oils made fromanimals, plants and microorganisms or synthesized oils. Specificexamples include lard, beef tallow, chicken oil, whale oil, fish oil,liver oil, soybean oil, cotton seed oil, safflower oil, rice oil, cornoil, rape seed oil, palm oil, beefsteak plant oil, Perilla ocimoidesoil, cacao butter, peanut oil, coconut oil, evening primrose oil, BorageOil, milk fat, butter and the oil made by blending synthesizedtriglyceride such as medium chain triglyceride or so.

Examples of the lipid include specific gravity moderators such asglycosylceramide, Octacosanol, phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,phytosterol, lycopene, beta-carotene, lutein, SAIB (sucrose aceticacid/isobutyric acid ester), etc.

Examples of other oily component include fat-soluble vitamins,oil-soluble flavor, hydrocarbons, etc. Specific examples of thefat-soluble vitamin include vitamin A, vitamin D, vitamin E, vitamin K,vitamin P, etc. Specific examples of the oil-soluble flavor includementhol, orange oil, lemon oil, Citrus junos oil, essential oil, etc.

Examples of the hydrocarbons include squalene, squalane, lanolin, liquidparaffin, etc.

In the invention, the amount of the oil, lipid and other oily componentsare not particularly limited because these do not affect use of coenzymeQ₁₀, but preferably 0.1-20% by weight.

Although the water-soluble composition containing coenzyme Q₁₀ of thepresent invention may be just used as oil-in-water type emulsion, forexample, it may be used as dry powder after removing moisture byspray-drying, etc. Where the dry powder is added into aqueous liquidsuch as water, the powder may immediately dissolve to give an aqueoussolution containing coenzyme Q₁₀. Where the powder is taken or consume,it will dissolve into water in the subject and resultantly form anaqueous solution.

The water-soluble composition of the present invention may be justconsume, it can be employed as a blending material for adding coenzymeQ₁₀ in various kinds of food. Its application is not particularlylimited, and it may be applicable to any kind of foods and beverages.

Examples of the foods containing the composition of the inventioninclude beverages such as refreshing drinks, sports beverage, carbonateddrinks, health drinks etc; noodles such as udon, spaghetti etc; breadsor sweets such as vegetable pancake, bread, cookie, candy, jelly etc;milk flesh processed food such as yogurt, Ham etc; seasoning such asMiso, sauce, liquid soup, mixed sauce, dressing oil etc; processed foodsuch as Tofu, noodles etc; oil processed food such as margarine, low-fatmargarine, shortening etc. The examples further include, inconsideration of its form, powder food such as powder beverage, powdersoup etc; health food product in the shape of capsule, tablet, powder,granule etc; other medicines, medical food, animal feed that areadministered as enrichment of nutrient.

Typical examples of the beverage include beverage comprising at leastone selected from saline or minerals such as table salt or iron,sourness, sweetener, alcohol, vitamin, flavor, and nectar; namely,refreshing drinks, sports beverage, juice, sour milk beverage, liquor,vitamin mineral beverage, health drink, etc. They further includeprocessed milk, soybean milk, beverage for use in improvement of human'sconstitution, beverage made by blending with a natural material whichcan expect physiology effect, thereof.

A convenience of intake prefers beverages such as refreshing drinks,health drinks, etc. These beverages are easily drunk anywhere, surelyreplenished to those weak senior citizens, dysphagia persons,alimentation of postoperatives and so on who have difficulty inconsuming solid, further expecting bioavailability improvement.

In the above application, the amount of coenzyme Q₁₀ is not particularlylimited, but preferably 0.001-80% by weight in the product.

Examples of cosmetics containing the water-soluble composition of theinvention include O/W type lotion, O/W type cream, viscous microemulsionessence, O/W type essence, etc. Various additives usually employable inthe technical fields, for example, anti-oxidant, ultraviolet radiationblocking agent, horny cell layer remover, surfactant, odorant, pigment,antiseptic, pH moderator, chelating agent and so on are appropriatelyblended into the cosmetics of the invention. The cosmetics of theinvention are employable in prevention from aging of skin, in preventionand amelioration of rough, dry skin.

This invention will be illustrated with reference to Examples, but notlimited thereto.

EXAMPLES

The measuring method and the evaluation method used will be illustratedbelow.

1. Measuring Method of an Average Particle Diameter

The average particle diameter of samples was determined by measuringdispersed particle using a submicron particle size distributionmeasuring apparatus [Type N4SD; Beckman Coulter, Inc.].

2. Acid Resistance & Heat Resistance Test

A water-soluble composition comprising coenzyme Q₁₀ was added in anamount of 1% by weight into purified water at pH 3 or less adjusted withcitric acid, and the acid aqueous solution containing the water-solublecomposition was incubated in a water bath for 30 minutes, from the timewhen the temperature reached to 85° C. The acid solution was cooled toroom temperature and the acid resistant & heat resistant property wasevaluated by its average particle diameter after 1 day.

3. Salt-Resistance & Heat Resistance Test

A water-soluble composition comprising coenzyme Q₁₀ was added in anamount of 1% by weight to purified water containing table salt of 5% byweight, and the salt solution was incubated for 30 min. in a water bathfrom the time when the temperature reached to 85° C., the salt solutionwas heat-treated for 30 minutes. The solution was cooled to roomtemperature and the salt-resistance & and heat resistance was evaluatedby its average particle diameter after 1 day.

Example 1

Decaglycerinmonooleate of 12% by weight, pentaglycerintrioleate of 5% byweight and water 78% by weight were warmed and dissolved completely toform an aqueous phase. Coenzyme Q₁₀ (Food material coenzyme Q₁₀, NissinPharma Inc.) of 5% by weight was gently added to the aqueous phase withstirring and subsequently the mixed solution was homogenized under 150MPa (1531 kg/cm²) with a high pressure homogenizer, thereby resultantlypreparing uniform water-soluble composition. The composition wasevaluated by the foregoing methods.

Constitution of the composition and results of the evaluation are shownin Table 1. In Table 1, “AA” means that uniformity is within ±10 nmwhere the particle diameter is smaller than 100 nm; and uniformity iswithin ±10% where the particle diameter is 100 nm or greater; exhibitingfavorable stability. “BB” means that uniformity is within ±20 nm wherethe particle diameter is smaller than 100 nm and uniformity is within±20% where the particle diameter is 100 nm or greater, exhibitingslightly poor stability. “CC” means that the stability is poor andreveals fluctuation outside of the above range.

Example 2

Decaglycerinmonooleate of 9.5% by weight, pentaglycerinmonooleate of6.5% by weight, water of 24% by weight and glucose-fructose liquid sugarof 50% by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ of 10% by weight was gently added to the aqueousphase with stirring and subsequently the mixed solution was processed at1500 m/minute of a blade peripheral speed for 15 min. with a homo-mixer,then, homogenized under 200 MPa (2039 kg/cm²) with a high pressurehomogenizer, thereby resultantly preparing uniform water-solublecomposition. The composition was evaluated in the same manner asExample 1. Constitution of the composition and results of evaluation areshown in Table 1.

Example 3

Decaglycerinmonooleate of 9.5% by weight, pentaglycerinmonooleate of6.5% by weight, water of 18% by weight and glucose-fructose liquid sugarof 52% by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ of 10% by weight and palm oil of 4% by weightpreparedly mixed and dissolved as oil phase were gently added to theaqueous phase with stirring and subsequently the mixed solution wasprocessed at 1500 m/minute of the blade peripheral speed for 15 minuteswith a homo-mixer, then, homogenized under 200 MPa (2039 kg/cm²) with ahigh pressure homogenizer, thereby resultantly preparing uniformwater-soluble composition. The composition was evaluated in the samemanner as Example 1. Constitution of the composition and results of theevaluation are shown in Table 1.

Example 4

Decaglycerinmonooleate of 9.5% by weight, pentaglycerinmonooleate of 4%by weight, citric acid monoglyceride of 2% by weight, water of 55.5% byweight and Gum Arabic of 19% by weight were warmed and dissolvedcompletely to form an aqueous phase. Coenzyme Q₁₀ of 10% by weight wasgently added to the aqueous phase with stirring and subsequently themixed solution was processed at 1800 m/minute of a blade peripheralspeed for 60 min. with a homo-mixer, thereby resultantly preparinghomogeneous water-soluble composition. The composition was evaluated inthe same manner as Example 1. Constitution of the composition andresults of the evaluation are shown in Table 1.

Example 5

Decaglycerinmonooleate of 13.5% by weight, hexaglycerinmonooleate of6.5% by weight, water of 31% by weight and reducing starch sugar of 30%by weight warmed and dissolved completely to form an aqueous phase.Coenzyme Q₁₀ of 15% by weight and SAIB of 4% by weight preparedly mixedand dissolved as an oil phase were gently added to the aqueous phasewith stirring and subsequently the mixed solution was processed at 1500m/minute of a blade peripheral speed for 15 minutes with a homo mixer,then, homogenized under 245 MPa (2500 kg/cm²) with a high pressurehomogenizer, thereby resultantly preparing uniform water-solublecomposition. The composition was evaluated in the same manner asExample 1. Constitution of the composition and results of the evaluationare shown in Table 1.

Example 6

Decaglycerinmonooleate of 13.5% by weight, tetraglycerinmonooleate of6.5% by weight, water of 31% by weight and reducing starch sugar of 30%by weight warmed and dissolved completely to form an aqueous phase.Coenzyme Q₁₀ of 15% by weight and SAIB of 4% by weight preparedly mixedand dissolved were gently added to the aqueous phase with stirring andsubsequently the mixed solution was processed at 1500 m/minute of ablade peripheral speed for 20 minutes with a homo mixer, then,homogenized under 245 MPa (2500 kg/cm²) with a high pressurehomogenizer, thereby resultantly preparing uniform water-solublecomposition. The composition was evaluated in the same manner asExample 1. Constitution of the composition and results of the evaluationare shown in Table 1.

Example 7

Decaglycerinmonooleate of 12.5% by weight, pentaglycerinmonooleate of8.5% by weight, water of 19% by weight and glucose-fructose liquid sugarof 30% by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ of 30% by weight was gently added to the aqueousphase with stirring and subsequently the mixed solution was homogenizedunder 150 MPa (1531 kg/cm²) with a high pressure homogenizer, then,homogenized under 200 MPa (2039 kg/cm²) with the homogenizer twice,thereby resultantly preparing uniform composition. The composition wasevaluated in the same manner as Example 1. Constitution of thecomposition and results of the evaluation are shown in Table 1.

Comparative Example 1

Comparative Example 1 was performed similarly as Example 1 except thatwere replaced by decaglycerinmonooleate of 17% by weight was used instead of decaglycerinmonooleate of 12% by weight andpentaglycerinmonooleate of 5% by weight thereby resultantly preparinguniform composition. The composition was evaluated in the same manner asExample 1. Constitution of the composition and results of the evaluationare shown in Table 1.

Comparative Example 2

Comparative Example 2 was performed similarly as Example 1 except thatwere replaced by decaglycerinmonostearate of 17% by weight was used instead of decaglycerinmonooleate of 12% by weight andpentaglycerinmonooleate of 5% by weight thereby resultantly preparinguniform composition. The composition was evaluated in the same manner asExample 1. Constitution of the composition and results of the evaluationare shown in Table 1.

Comparative Example 3

Decaglycerimonooleate 3% by weight, pentaglycerinmonoolete of 0.5% byweight, water of 34.5% by weight and glucose-fructose liquid sugar of52% by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ of 10% by weight was added to the aqueous phase withstirring and subsequently the mixed solution was processed at 1500m/minute of a blade peripheral speed for 15 minutes with a homo-mixer,then, homogenized under 200 MPa (2039 kg/cm²) with a high pressurehomogenizer, thereby resultantly preparing uniform composition. Thecomposition was evaluated in the same manner as Example 1. Constitutionof the composition and results of the evaluation are shown in Table 1.

Comparative Example 4

Decaglycerinmonooleate of 40% by weight, pentaglycerinmonoolete of 20%by weight and water of 30% by weight were warmed and dissolvedcompletely to form an aqueous phase. Coenzyme Q₁₀ of 10% by weight wasgently added to the aqueous phase with stirring and subsequently themixed solution was processed at 1500 m/of a blade peripheral speed for15 minutes with a homo-mixer, then, homogenized under 200 MPa (2039kg/cm²) with a high pressure homogenizer, however, failed in forming anywater-soluble composition because the viscosity of the resultantcomposition was considerably high.

In Tables, “Ex.”, “Co. Ex.”, “B. C.” and “R.” means “Example”,“Comparative Example”, “Blending Cnsituents” and “Results” each as theirabbreviation respectively. TABLE 1 Constitution (%) of water-solublecomposition and Results Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Co.Ex. 1 Co. Ex. 2 Co. Ex. 3 Co. Ex. 4 B. C A Coenzyme Q:10 5 10 10 10 1515 30 5 5 10 10 B Decaglycerinmonooleate 12 9.5 9.5 9.5 13.5 13.5 12.517 3 40 C Pentaglycerintrioleate 5 C Pentaglycerinmonooleate 6.5 6.5 48.5 0.5 20 C Hexaglycerinmonooleate 6.5 C Tetraglycerinmonooleate 6.5Others Citric acid monoglyceride 2 Others Decaglycerinmonostearate 17 DWater 78 24 18 55.5 31 31 19 78 78 34.5 30 E Glucose-fructose liquidsugar 50 52 30 52 E Gum Arabic 19 E Reducing starch sugar 30 30 OthersPalm Oil 4 Others Specific gravity moderator 4 4 Sum 100 100 100 100 100100 100 100 100 100 100 A/(B + C) 1/3.4 1/1.6 1/1.6 1/1.6 1/1.3 1/1.31/0.7 1/3.4 1/3.4 1/0.4 1/6 B/C 1/0.4 1/0.7 1/0.7 1/0.4 1/0.5 1/0.51/0.7 — — 1/0.2 1/0.5 R. Particle Diameter (nm) 108.0 49.5 48.2 76.558.3 68.0 88.0 107.0 126.0 473.0 Disabled* Acid resistance 103.0 49.349.5 75.8 57.2 63.7 86.0 112.0 120.0 488.0 — Acid resistance & heatresistance 101.0 50.9 58.2 76.0 60.2 63.0 95.9 120.0 134.0 Separation —Evaluation results AA AA AA AA AA AA AA BB BB CC — Salt-resistance 101.049.7 49.1 75.5 58.5 64.1 85.0 109.0 122.0 483.0 — Salt-resistance & heatresistance 102.0 51.1 58.0 77.5 62.7 70.6 97.2 135.0 138.0 Separation —Evaluation results AA AA AA AA AA AA AA CC BB CC —*Preparation disabled because of over viscosity

The above results revealed that compositions of Comparative Example 1wherein the solubilizer was decaglycerinmonooleate only and ComparativeExample 2 wherein the particle diameter was 110 nm or greater areinferior in acid resistant & heat resistant properties and insalt-resistant & heat resistant properties.

The composition of Comparative Example 3 wherein the amounts of (B)decaglycerinmonooleate and (C) pentaglycerinmonooleate were less thanthe range defined in the invention has large particle diameter of thecomposition and is inferior in acid resistant & heat resistantproperties and salt-resistant & heat resistant properties.

In Comparative Example 4 wherein the amounts of (B)decaglycerinmonooleate and (C) pentaglycerinmonooleate were greater thanthe range defined in the invention, it was impossible to prepare anystable water-soluble composition.

On the contrary, it is apparently verified that Examples 1-7 accordingto the invention succeeded in preparing the water-soluble compositionwith the particle diameter of 110 nm or smaller, good stably andsuperior in acid resistant & heat resistant properties andsalt-resistant & heat resistant properties.

Example 8

Decaglycerinmonostearate of 16% by weight, pentaglycerinmonostearate of4% by weight, water of 20% by weight and glucose-fructose liquid sugarof 50% by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ as an oil phase of 10% by weight was gently added tothe aqueous phase with stirring and subsequently the mixed solution wasprocessed treated at 1500 m/minute of a blade peripheral speed for 15minutes with a homo-mixer, then, homogenized under 200 MPa (2039 kg/cm²)with a high pressure homogenizer, thereby resultantly preparing uniformcomposition.

The composition was evaluated in the same manner as Example 1.Constitution of the composition and results of the evaluation are shownin Table 2.

Example 9

Decaglycerinmonooleate of 16% by weight, pentaglycerinmonostearate of 4%by weight, water of 20% by weight and glucose-fructose liquid sugar of50% by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ of 10% by weight was gently added to the aqueousphase with stirring and subsequently the mixed solution was processed at1500 m/minute for 15 minute with a homo-mixers, then, homogenized under200 MPa (2039 kg/cm²) with a high pressure homogenizer, therebyresultantly preparing uniform composition. The composition was evaluatedin the same manner as Example 1. Constitution of the composition andresults of the evaluation are shown in Table 2.

Example 10

Decaglycerinmonostearate of 8% by weight, decaglycerinmonolinoleate of8% by weight, pentaglycerinmonostearate of 4% by weight, water of 20% byweight and glucose-fructose liquid sugar of 46% by weight were warmedand dissolved completely to form an aqueous phase. Coenzyme Q₁₀ of 10%by weight and palm oil of 4% by weight preparedly mixed and dissolved asan oil phase were gently added to the aqueous phase with stirring andsubsequently the mixed solution was processed at 1500 m/minute of ablade peripheral speed for 15 minutes with a homo-mixer, then,homogenized under 200 MPa (2039 kg/cm²) with a high pressurehomogenizer, thereby resultantly preparing uniform composition. Thecomposition was evaluated in the same manner as Example 1. Constitutionof the composition and results of the evaluation are shown in Table 2.

Example 11

Decaglycerinmonooleate of 8% by weight, decaglycerinmonolinoleate of 8%by weight, pentaglycerinmonooleate of 4% by weight, water of 20% byweight and glucose-fructose liquid sugar of 46% by weight were warmedand dissolved completely to form an aqueous phase. Coenzyme Q₁₀ as anoil phase of 10% by weight was gently added to the aqueous phase withstirring and subsequently the mixed solution was processed at 1500m/minute of a blade peripheral speed for 15 minutes with a homo-mixer,then, homogenized under 200 MPa (2039 kg/cm²) with a high pressurehomogenizer, thereby resultantly preparing uniform composition. Thecomposition was evaluated in the same manner as Example 1. Constitutionof the composition and results of the evaluation are shown in Table 2.TABLE 2 Composition (%) of water-soluble composition Ex. 8 Ex. 9 Ex. 10Ex. 11 B.C. A Coenzyme Q10 10 10 10 10 B Decaglycerin 16 8 monostearateB Decaglycerin 16 8 monooleate B Decaglycerin 8 8 monolinoleate CPentaglycerin 4 4 4 monostearate C Pentaglycerin 4 monooleate D Water 2020 20 20 E Glucose-fructose 50 50 46 50 Liquid sugar Others Palm Oil 4Sum 100 100 100 100 A/(B + C) 1/2 1/2 1/2 1/2 B/C 1/0.25 1/0.25 1/0.251/0.25 R. Particle 69.2 59.6 80.6 78.3 Diameter (nm) Acid resistance66.1 62.5 89.3 81.3 Acid resistance & 67.1 62.6 88.4 79.9 heatresistance Evaluation AA AA AA AA Salt-resistance 66.7 60.3 88.6 78.4Salt-resistance & 65.5 62.8 86.7 81.1 heat resistance Evaluation AA AAAA AA

As the results, it is verified that Examples 8 to 11 wherein at leastone oleic acid ester in Component (B) or (C) was substituted with theother fatty acid ester having 18 carbon atoms or its mixture alsosucceeded in preparing the water-soluble composition having the particlediameter of 110 nm or smaller, good stably and superior in acidresistant & heat resistant properties and salt-resistant & heatresistant properties.

Example 12

A beverage consisting of the water-soluble composition of Example 2 orExample 3 of 0.3% by weight, glucose-fructose liquid sugar of 15% byweight, granulated sugar of 7% by weight, 5 times concentratedgrapefruit juice of 4% by weight, citric acid of 0.3% by weight, sodiumcitrate of 0.2% by weight, grapefruit flavor of 0.2% by weight and waterof 73% by weight it was prepared, filled into a 100 ml bottle and then,sterilized at 85° C. for 30 minutes.

De-emulsion of coenzyme Q₁₀ was not recognized after the sterilizationand the beverage was drinkable without any problem.

Comparative Example 5

Tetraglycerinmonostearate of 9 parts by weight, decaglycerinmonostearateof 6 parts by weight, glycerin of 5 parts by weight and water of 70parts by weight were warmed and dissolved completely to form an aqueousphase. Coenzyme Q₁₀ of 10 parts by weight was gently added to theaqueous phase with stirring and subsequently the mixed solution wasprocessed for 5 minutes with a homo-mixer, thereby resultantly preparinga dispersed solution of coenzyme Q₁₀ having average particle diameter of380 nm. The emulsified state just after the preparation was good,however, de-emulsion was found in the upper part 2 weeks later.

Comparative Example 6 Emulsified Powders

Coenzyme Q₁₀ of 100 g was melted by warming and added into 200 g ofglucose fatty acid ester preparedly melted by warming at 60° C. and theywere further emulsified. After passing them through high pressurehomogenizer (H-11; SANWA MACHINE CO., INC.), they were atomized duringflowing excipient mixture consisting of milk sugar of 1000 g and starchof 700 g with a fluidized-bed type granulator (FLO-MINI; FreundCorporation) to form orange colored powdery or granular composition.Throwing 1 g of the powder composition into 100 g of water immediatelydispersed and dissolved to give pale yellowish dispersion comprisingcoenzyme Q₁₀. By measuring the particle diameter of the dispersedcoenzyme Q₁₀ in the dispersion, a 50% particle diameter was 2.62 μm.

Comparative Example Soft Capsule

Coenzyme Q₁₀ of 60 g, soybean oil of 240 g and glycerin fatty acid ester(COCONARD MT) of 300 g were warmed and dissolved at 60° C. Afterassuring the dissolution of coenzyme Q₁₀, the mixed solution was cooledto around 25° C., thereby preparing capsule filling fluid. Subsequently,soft capsules each containing 30 mg of coenzyme Q₁₀ were prepared usingthe conventional technique.

Reference Test 1

The water-soluble compositions of Example 2 and Comparative Example 5were compared with respect to absorbency of coenzyme Q₁₀ by animal test.

<Absorption Test on Animals>

Two groups of 3 beagle dogs (males) per group were employed for theabsorption test. Fasting from after 17:00 in the day beforeadministration, hard capsules containing the composition of Example 2and the dispersion of Comparative Example 5 with coenzyme Q₁₀ 90 mg/dogof dosage respectively were forcedly administrated to all the dogs once.Sampling blood regularly until 24 hours after the administration, theconcentration of coenzyme Q₁₀ in plasma were determined. The results areshown in Table 3.

<Method for Measuring Coenzyme Q₁₀ in Plasma>

The measurement of coenzyme Q₁₀ in plasma was carried out using HighPerformance Liquid Chromatography (HPLC) under the following conditions.Additionally, because there are both oxidized and reduced types ofcoenzyme Q₁₀ in plasma, the samples were subjected to the measurement byHPLC after converting reduced type to oxidation type by adding ironoxide.

<HPLC Condition>

-   Column: Nucleosil 5C18, 4.6 mm φ×25 cm,-   Moving phase: Ethanol/Acetonitrile (=60/40 volume ratio),-   Flow rate: 1 ml/minute,-   Detector: UV spectroscopy photometer,

Detecting wave length=275 nm. TABLE 3 Reference Test Sample Ex. 2 Co.Ex. 6 (Particle Diameter) 49.5 nm 380 nm Cmax 1.172 ± 1.72  0.583 ±2.01  (μg/ml) tmax (hr) 5.88 ± 0.9  6.24 ± 1.2  AUC (O→t) 11.2 ± 0.676.31 ± 0.88 (μg · hr/ml)Cf. Cmax (μg/ml): Maximum concentration in bloodtmax (hr): Time until maximum concentration in blood

AUC (0→24) (μg·hr/ml): Area under curve of drug concentration inblood/time.

As the results, it is verified that bioabsorbency was significantly highin the case where the water-soluble composition of Example 2 havingsmaller particle diameters was administered, in comparison with thedispersion of Comparative Example 5. Absorbency of coenzyme Q₁₀ duringfasting was usually considered poor, however, it is confirmed that theadministration of the water-soluble composition containing coenzyme Q₁₀having small particle diameters of the invention may conspicuouslyimprove its bioabsorbency.

Reference Test 2; Absorbency Test During Fasting

The absorbency test during fasting was carried out by oraladministration of the water-soluble composition of Example 2, theemulsified powder composition of Comparative Example 6 or the softcapsule of Comparative Example 7 each to three subjects respectively.

Fasting from after 21:00 on day before the administration, coenzyme Q₁₀60 mg was orally administered to the subjects at 8:00 on next morningunder fasting. Sampling blood 2, 4, 6, 8, 12 and 24 hours after theadministration, the concentration of coenzyme Q₁₀ in blood weremeasured. The measurement of the concentration was carried out usingHPLC under the following conditions. Because there are both oxidiedandreduced types of coenzyme Q₁₀ in blood, the concentration weredetermined by adding the measured values of both types.

-   Column: Nhdeosil 5C18 4.6 mm×25 cm-   Moving phase: ethanol: acetonitrile (55:45):-   Flow rate: 1 ml/minute-   Detector: UV spectroscopy photometer 275 nm

Results show that both the emulsified powder composition of ComparativeExample 6 and the soft capsule of Comparative Example 7 gave extremelylittle rise of the concentration in blood after the administration andwere almost not absorbed. However, it is confirmed that thewater-soluble composition of Example 2 may give bioabsorption ofcoenzyme Q₁₀ surely with high level even by the administration underfasting. Although the previous knowledge teaches that absorption ofcoenzyme Q₁₀ was not achieved unless consuming together with eating, itis confirmed that the water-soluble composition according to theinvention may conspicuously improve the absorbency even under fasting.These results are shown in FIG. 1.

Reference Test 3; Absorbency Test After Eating

The absorbency test after eating was carried out by oral administrationof the composition of Example 2, the emulsified powder composition ofComparative Example 6 and the soft capsule of Comparative Example 7 eachto three subjects respectively.

After finishing a meal until 22:00 on day before the administration,blood was sampled from each subject respectively in the next morning,and then, 60 mg of coenzyme Q₁₀ was orally administered to the subjectswithin 10 minutes after the breakfast. Sampling blood 2, 4, 6, 8, 12 and24 hours after the administration, the concentrations of coenzyme Q₁₀ inblood were measured in the same manner as Reference Test 2.

Results show that both the emulsified powder composition of ComparativeExample 6 and the soft capsule of Comparative Example 7 initiatedelevation of the concentration two hours after the administration, thecomposition of Example 2 initiated elevation immediately after theadministration and exhibited extremely faster rise of the increase inthe absorbed amount than the comparative examples. It is confirmed thatthe water-soluble composition of the invention was extremely superior inbioabsorbency. These results are shown in FIG. 2.

INDUSTRIAL APPLICABILITY

The water-soluble composition containing coenzyme Q₁₀ according to thepresent invention is superior in storage stability, and is capable ofmaintaining an uniform and stable state without precipitating coenzymeQ₁₀ during a long term storage. The composition of the invention issuperior in acid resistance, salt-resistance and heat resistance, andfurther enables to maintain good water-soluble state even blending tomedicines, foods and beverages, cosmetics, feeds, additives usuallyemployed therein. The composition is stable against heating, andacceptable of high-temperature disinfection or sterilization.Furthermore, the composition of the invention is conspicuously improvedin absorbency of coenzyme Q₁₀ Particularly, sufficient amounts ofcoenzyme Q₁₀ can be consumed even when being hungry.

Although the water-soluble composition of the invention may be directlyconsumed, blending it to medicines, foods and beverages, cosmetics orfeeds may achieve effective adsorption of sufficient amount of coenzymeQ₁₀. Particularly, the composition can surely supply coenzyme Q₁₀ tothose weak senior citizens, dysphagia persons, alimentation ofpostoperatives who have difficulty swallowing of solid matters.

1. A water-soluble composition which comprises (A) coenzyme Q₁₀ of 5 to40% by weight, (B) monoester of polyglycerol with averagedpolymerization degree of 10 and fatty acid having 18 carbon atoms of 5to 30% by weight, (C) mono-, di-, tri- or penta-ester of polyglycerolwith average polymerization degree of 3-6 and fatty acid having 18carbon atoms of 1 to 18% by weight, and (D) water wherein its averagedparticle diameter is 110 nm or smaller.
 2. The water-soluble compositionof claim 1, wherein said fatty acid composing component (B) is stearicacid, oleic acid or linoleic acid, and wherein said fatty acid composingcomponent (C) is stearic acid, oleic acid or linoleic acid.
 3. Thewater-soluble composition of claim 1, further comprises (E) asolubilizer of 10 to 80% by weight.
 4. The water-soluble composition ofclaim 3, wherein said solubilizer is gum, saccharide or polyhydricalcohol.
 5. The water-soluble composition of claim 1, wherein a weightratio [(A)]/[(B)+(C)] of is within the range of 1/(5-0.7) and wherein aweight ratio of [(B)]/[(C)] is within the range of 1/(0.2-1).
 6. Aprocess for producing the water-soluble composition according to claim 1which comprises the steps of: (I) heating and dissolving the components(B), (C), (D) and optionally the component (E); (II) adding component(A) and mixing; and at least one selected from (III) homogenizing theresultant mixture with a shear force of 750 m/minute or greater as aperipheral-speed of an agitation blade using a homo-mixer; or (IV)homogenizing the resultant mixture under a homogenizing pressure of 98MPa (1,000 kg/cm²) or greater using a homogenizer.
 7. The process ofclaim 6, wherein said step (III) or (IV) is repeated, or wherein thesteps (III) and (IV) are successively carried out.
 8. Medicinescontaining said water-soluble composition described in claim
 1. 9. Foodsand beverages containing said water-soluble composition described inclaim
 1. 10. Cosmetics containing said water-soluble compositiondescribed in claim
 1. 11. Feeds containing said water-solublecomposition described in claim
 1. 12. The water-soluble composition ofclaim 2, further comprises (E) a solubilizer of 10 to 80% by weight. 13.The water-soluble composition of claim 12, wherein said solubilizer isgum, saccharide or polyhydric alcohol.